A member of the epidermal growth factor (hereinafter referred to as EGF) family purified by Toyoda et al. was named “epiregulin (EREG)”. EREG is known to function as a cancer growth inhibitor that induces morphological changes of HeLa cells (Non-Patent Document 1). The amino acid sequence of mouse-derived EREG (mature protein) purified by Toyoda et al. consists of 46 amino acid residues, and shares a sequence identity of about 24% to 50% with other members of the EGF family. Mouse EREG showed low affinity to the EGF receptor on A431 cells (a human epithelial carcinoma cell line). The cloning and expression analysis of the human EREG gene by Toyoda et al. showed that, while other members of the EGF family are expressed ubiquitously in human tissues, the EREG expression is detectable in macrophages, placenta, and various types of cancer cells (Non-Patent Document 2). In addition, the soluble form of EREG was shown to have proliferation-suppressing effect on several types of cancer cells (WO94/29340).
Takahashi et al. showed that the activation of Erk (MPK3) and p38 (MAPK14) in differentiated arterial vascular smooth muscle cells (hereinafter referred to as VSMC) from rats induces dedifferentiation of the cells. Furthermore, it was demonstrated that EREG secreted by VSMC acts as an autocrine and/or paracrine differentiation factor. Unsaturated lysophosphatidic acid and PDGFB homodimer, which may act as differentiation factors of VSMC, rapidly up-regulated the mRNA expression of EREG in an Erk− and p38 MAPK-dependent manner. Reverse transcriptase polymerase chain reaction (hereinafter referred to as RT-PCR) analysis, and immunohistochemical or immunohistochemistry (hereinafter referred to as IHC) analysis revealed localized EREG expression in atherosclerotic arteries and balloon-injured rat arteries. From these results, Takahashi and others speculated that EREG might be involved in the progression of vascular remodeling such as atherosclerosis (Non-Patent Document 3).
Minn et al. identified several gene clusters related to lung metastasis of breast cancer based on in vivo selection, transcriptome analysis, functional analysis, and clinical research, and showed that EREG is one of the genes (Non-Patent Document 4).
Furthermore, Shirasawa et al. showed that EREG is expressed not only in keratinocytes but also in tissue macrophages, and that EREG-knockout mice develop chronic dermatitis. Examinations in the analysis of these mice revealed that EREG plays an important role in immunity- and inflammatory-related responses of keratinocytes and macrophages at the boundary with the external environment (Non-Patent Document 5).
As described above, the connection between EREG and dermatitis, cancer metastasis, and atherosclerosis has been indicated. However, there are still no specific descriptions on the effect of EREG-binding antibodies that have neutralizing activity and cytotoxic activity on EREG-expressing cancer cells.    [Non-Patent Document 1] J. Biol. Chem. 270: 7495-7500, 1995    [Non-Patent Document 2] Biochem. J. 326: 69-75, 1997    [Non-Patent Document 3] Circulation 108: 2524-2529, 2003    [Non-Patent Document 4] Nature 436: 518-524, 2005    [Non-Patent Document 5] Proc. Nat. Acad. Sci. 101: 13921-13926, 2004